Phosphonates are derivatives of the hypothetical phosphonic acid, HP(O)(OH).sub.2, and have been widely investigated as models for phosphate esters because they have an approximately isoteric relationship and because the C-C-P linkage is more resistant to hydrolysis than is the C-O-P linkage. Monofluoro and difluoro methanediphosphonic acids are useful as carbon analogs of pyrophosphoric acid in that the fluorinated methane group is equal to the central oxygen atom of pyrophosphoric acid, but the P-C-P bonds cannot be easily broken by enzymes or other means.
As pyrophosphate analogs, fluorinated methanediphosphonic acids are useful in biological and medical applications with respect to bone disorders and other circumstances involving pyrophosphate metabolism. The alpha fluorination of the diphosphonic esters heightens their similarity to the corresponding phosphoric acid esters. This is due to the fact that the fluorinated alpha-CH.sub.2 group has an electro-negativity which is similar to that of oxygen in the phosphoric acid compounds. Specific examples of useful biological-medical applications include the treatment of Paget's disease and osteoporosis of bone, the bone-specific delivery of chelated radioactive metal ions and drug-active moieties.
While the direct halogenation of tetra-alkyl methanediphosphonates is a proven method for the preparation of mono and dichloro, bromo and iodo derivatives, methods for the direct fluorination of such esters have shown poor results. The use of fluorine gas, perfluoropiperidine or perfluoro 2,6-dimethylpiperidine have each led to partial fluorine substitution for hydrogen at all possible sites in tetraethyl methanediphosphonate. Tetraethyl difluoro methanediphosphonate has been prepared with a 12% overall yield from dibromo difluoromethane and sodium diethylphosphonate via diethyl bromodifluoro methanephosphonate.
According to the present invention, a direct method to fluorinated alkanediphosphanates is provided by the reaction of alkanediphosphonate esters with perchloryl fluoride. Perchloryl fluoride reacts smoothly with tetraalkyl or tetraaromatic lower alkanediphosphonate carbanions to form the corresponding fluorophosphonate esters. The diphosphonate carbanion is produced by a strong base such as sodium, sodium hydride or sodium ethoxide, but if potassium tert-butoxide is used as a base, the total yield of fluorinated phosphonate esters approaches 85%.
The fluorination reaction proceeds virtually as a titration of base with perchloryl fluoride and shows a readily recognizable end point marked by a characteristic color change from dark to pale yellow. Termination of the reaction is also indicated by the end of a temperature rise accompanying the reaction and cessation of perchloryl fluoride uptake.
Hydrolysis of the monofluoro and difluoro diphosphonate esters yields the respective fluoro alkanediphosphonic acid and difluoro alkanediphosphonic acid. As an example, when compared with the parent methanediphosphonic acid, these new compounds show a smooth trend of decreasing melting point and increased nuclear magnetic shielding at phosphorous as the alpha hydrogen atoms of methanediphosphonic acid are replaced by fluorine atoms relative to H.sub.3 PO.sub.4.
The methanediphosphonate ester is first reacted with the base to form a carbanion EQU [(RO).sub.2 P(O)].sub.2 CH.sup.-
(I)
which reacts with FClO.sub.3 to form the monofluoro ester EQU [(RO).sub.2 P(O)].sub.2 CFH (II)
Further treatment with the base yields a second carbanion EQU [(RO).sub.2 P(O)].sub.2 CF.sup.- (III)
which reacts similarly upon exposure to FClO.sub.3 to form the difluoro ester EQU [(RO).sub.2 P(O)].sub.2 CF.sub.2 (IV)
Hydrolysis of the methanediphosphonic esters to the corresponding diphosphonic acids may be accomplished by any one of a number of methods known in the art. A preferred method is the treatment of the esters II and IV with bromotrimethylsilane to produce the trimethylsilyl esters EQU [(TMSO).sub.2 P(O)].sub.2 CFH (V)
and EQU [(TMSO).sub.2 P(O)].sub.2 CF.sub.2 (VI)
respectively.
Hydrolysis of the esters V and VI affords, respectively, fluoro methanediphosphonic acid EQU [(HO).sub.2 P(O)].sub.2 CFH (VII)
and difluoro methanediphosphonic acid EQU [(HO).sub.2 P(O)].sub.2 CF.sub.2 (VIII)
In the above formulas, R may be any alkyl or aromatic group and the choice of the group R has been shown to have no effect upon the fluorination reactions of the present invention. Thus, R may be methyl, ethyl, propyl, butyl, benzyl, phenyl or a higher group as desired.
In another aspect of the invention, unsymmetrical fluorinated methanediphosphonate esters are synthesized and selectively hydrolized to form unsymmetrical diphosphonic acids i.e., half-acids. In a reaction similar to that described above, unsymmetrical unfluorinated ester carbanions having the formula ##STR1## react with FClO.sub.3 to form EQU (RO).sub.2 P(O)--CFH--P(O)(OR.sub.x).sub.2 (X)
and, alternatively, react further to form EQU (RO).sub.2 P(O)--CF.sub.2 --P(O)(OR.sub.x).sub.2 (XI)
R and R.sub.x, while dissimilar, may be any alkyl or aromatic group, although methyl, ethyl, propyl, butyl, benzyl or phenyl may be preferred as more complex groups offer no advantage with respect to the basic fluorination reaction.
Treatment with bromotrimethylsilane, as described, or other selective hydrolysis of the esters X and XI, respectively, yields the unsymmetrical half-esters ##STR2## and ##STR3##
With regard to the formation of the half-esters XII and XIII, R and R.sub.x are selected on the basis that the group having the smaller steric bulk will be converted first to the acid i.e., when R is isopropyl and R.sub.x is methyl, the reaction of R.sub.x proceeds first to produce bis-diisopropyl mono- or difluoro methanediphosphonic acid. Similarly, the silyldealkylation and hydrolysis reaction prefers primary carbon groups over secondary over tertiary, so that propyl groups will convert before isopropyl and isopropyl in turn, before t-butyl. The preferred R.sub.x is methyl due to its low steric bulk and primary form.
Other methods of selective hydrolysis may reverse the above described preference and convert the larger group to the acid before the smaller. R, R.sub.x and the hydrolysis method may each be selected as circumstances suggest or render expedient.